Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan

Background: Patient responsiveness to erythropoiesis-stimulating agents (ESAs), notoriously difficult to measure, has attracted attention for its association with mortality. We defined categories of ESA responsiveness and attempted to clarify their association with mortality.

Study design: Cohort study.

Setting & participants: Data from Japan's dialysis registry (2005-2006), including 95,460 adult hemodialysis patients who received ESAs.

Predictor: We defined 6 categories of ESA responsiveness based on a combination of ESA dosage (low [<6,000 U/wk] or high [≥6,000 U/wk]) and hemoglobin level (low [<10 g/dL], medium [10-11.9 g/dL], or high [≥12 g/dL]), with medium hemoglobin level and low-dose ESA therapy as the reference category.

Outcomes: All-cause and cardiovascular mortality during 1-year follow-up.

Measurements: HRs were estimated using a Cox model for the association between responsiveness categories and mortality, adjusting for potential confounders such as age, sex, postdialysis weight, dialysis duration, comorbid conditions, serum albumin level, and transferrin saturation.

Results: Median ESA dosage (4,500-5,999 U/wk) was used as a cutoff point, and mean hemoglobin level was 10.1 g/dL in our cohort. Of 95,460 patients during follow-up, 7,205 (7.5%) died of all causes, including 5,586 (5.9%) cardiovascular deaths. Low hemoglobin levels and high-dose ESA therapy were both associated with all-cause mortality (adjusted HRs, 1.18 [95% CI, 1.09-1.27] for low hemoglobin level with low-dose ESA and 1.44 [95% CI, 1.34-1.55] for medium hemoglobin level with high-dose ESA). Adjusted HRs for high-dose ESA with low hemoglobin level (hyporesponsiveness) were 1.94 (95% CI, 1.82-2.07) for all-cause and 2.02 (95% CI, 1.88-2.17) for cardiovascular mortality. We also noted the interaction between ESA dosage and hemoglobin level on all-cause mortality (likelihood ratio test, P = 0.002).

Limitations: Potential residual confounding from unmeasured factors and single measurement of predictors.

Conclusions: Mortality can be affected by ESA responsiveness, which may include independent and interactive effects of ESA dose and hemoglobin level. Responsiveness category has prognostic importance and clinical relevance in anemia management.